This is a request for continuation of a Research Scientist Award. My broadest objectives are to understand why people take psychoactive drugs, what are usual and expected effects, what might account for unexpected consequences, and how might adverse consequences best be managed. For example, how might tolerance and dependence determine individual differences in drug use and drug effects? Individual projects study the pharmacokinetics and pharmacodynamics of cocaine and methamphetamine administered by various routes, and their interactions with ethanol. The pharmacokinetics and cardiovascular, autonomic, EEG, neuroendocrine and subjective effects of substituted phenethylamines, 3,4-methylene- dioxymethamphetamine (MDMA) and related compounds will be compared to lysergic acid diethylamide (LSD), methamphetamine and cocaine. Modification of tolerance and dependence associated with cocaine and methamphetamine administration by new and novel treatment medications will be studied. The pharmacokinetics of deuterium-labeled cocaine, cocaethylene, morphine and methamphetamine in hair, skin, sweat, sebum and plasma will be- characterized to better understand mechanisms by which drugs enter hair and to judge the utility of analysis of hair and sweat as biomarkers of drug exposure. Characterization of the pharmacokinetics and dynamics of buprenorphine and its interactions with naloxone and factors altering such effects is studied as part of the evaluation of new pharmacologic treatments for opiate, cocaine and related dependence. As is possible, equal attention is given to psychological and behavioral measures, assessment of mood, neurophysiological and neurochemical indices. in the clinical studies, emphasis is on understanding relationships between behavioral, physiologic and pharmacologic variables. Biochemical, physiologic, neuroendocrinologic, behavioral and psychometric techniques are used to assess consequences of acute and subchronic drug administration. Recognizing that people rarely limit drug taking to a single drug or class of drugs, development and application of research strategies appropriate to the study of multiple classes of drugs rather than specialization with a particular methodology or drug class is a guiding philosophy. Where possible, mechanisms and explanations for individual differences in drug effects are studied. Relationships between naturally occurring and drug-induced disorders (for example, depression, anxiety states and schizophrenia or other psychosis) remains a topic of interest. The studies are multidisciplinary and involve only human subjects. They should further understanding of human psychoactive drug use, its health consequences and its management.